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Expression of hypoxia-inducible factors in human renal cancer: Relationship to angiogenesis and to the von Hippel-Lindau gene mutation.
2957 - 2961.
The von Hippel-Lindau tumor suppressor protein acts as the substrate recognition component of a ubiquitin E3 ligase that targets hypoxia-inducible factor (HIF)-alpha subunits for proteolysis. Stabilization of HIF-alpha subunits has been described in VHL-defective cell lines, leading to HIF activation and up-regulation of hypoxia-inducible mRNAs. Mutations of the von Hippel-Lindau tumor suppressor protein are found in most clear cell renal cell carcinomas (CC-RCCs) but not other renal tumors, raising a question about the importance of activation of the HIF pathway in CC-RCC development. To address this question, we have examined the expression of HIF-alpha subunits in 45 primary renal tumors and related this to tumor subtype, the presence of VHL mutations, and measures of angiogenesis. We show that HIF-alpha is up-regulated in the majority of CC-RCCs, and that the pattern of expression is biased toward the HIF-2alpha isoform. Expression of HIF-alpha proteins was associated significantly with up-regulation of VEGF mRNA and protein and increased microvessel density. Up-regulation of HIF-alpha in CC-RCC was found to involve increased mRNA as well as protein expression, suggesting that both VHL-dependent and VHL-independent mechanisms are involved. These results suggest that activation of the HIF pathway is functionally important in CC-RCC development and might provide a new therapeutic target.
|Title:||Expression of hypoxia-inducible factors in human renal cancer: Relationship to angiogenesis and to the von Hippel-Lindau gene mutation|
|Keywords:||ENDOTHELIAL GROWTH-FACTOR, TUMOR-SUPPRESSOR GENE, PAS DOMAIN PROTEIN-1, FACTORS HIF-1-ALPHA, MESSENGER-RNA, UP-REGULATION, FACTOR-1-ALPHA, TRANSCRIPTION, CARCINOMA, CELLS|
|UCL classification:||UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
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